Oral Presentation The 44th Lorne Conference on Protein Structure and Function 2019

The molecular basis of JAK/STAT inhibition by SOCS1 (#15)

Nicholas PD Liau 1 2 , Artem Laktyushin 1 , Isabelle S Lucet 1 2 , James M Murphy 1 2 , Shenggen Yao 3 , Eden Whitlock 1 2 , Kimberley Callaghan 1 2 , Nicos A Nicola 1 2 , Jeff J Babon 1 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. The University of Melbourne, Parkville, VIC, Australia

Cytokine signalling controls a diverse range of cellular processes, such as blood cell development, cell proliferation and the immune response. It is important that cytokine signalling is tightly regulated by the cell, as excessive signalling can lead to inflammation and proliferative diseases, including a group of blood diseases known as the myeloproliferative neoplasms (MPNs). The Janus Kinases (JAKs) are a family of four intracellular proteins which are key components of the cytokine signalling pathway. They function by phosphorylating downstream proteins in response to cytokine stimulation. The Suppressors of Cytokine Signalling (SOCS) are negative regulators of cytokine signalling. SOCS1 is known to downregulate multiple cytokine signalling pathways, including IFN-ɣ, IL-2 and IL-21. It is able to do so by downregulating JAK1, JAK2 and TYK2 (but not JAK3) by directly inhibiting JAK catalytic activity through a motif known as the Kinase Inhibitory Region (KIR).

We have recently undertaken the first structural and biochemical characterisation of SOCS1. We have shown that SOCS1 is a potent (low nM) and specific JAK inhibitor. The crystal structure of SOCS1 bound to JAK1 demonstrates that it inhibits JAK1 catalytic activity by blocking substrate access to its active site with its KIR domain. Key residues within the KIR, as identified from the structure and through functional mutagenesis studies, provide a template for the development of a new class of JAK inhibitors which could be used as more effective treatments for MPNs.

Other SOCS family members are known to bind to specific phosphotyrosine containing motifs on cytokine receptors. We have also shown that SOCS1 acts by a novel mechanism whereby it targets the phosphorylated activation loop of JAKs, resulting in a broad downregulation profile of cytokine pathways.

  1. Liau NPD, Laktyushin A, Lucet IS, Murphy JM, Yao S, Whitlock E, Callaghan K, Nicola NA, Kershaw NJ, Babon JJ., The molecular basis of JAK/STAT inhibition by SOCS1. Nat Commun. 2018 Apr 19;9(1):1558.
  2. Kershaw NJ, Murphy JM, Liau NPD, Varghese LN, Laktyushin A, Whitlock EL, Lucet IS, Nicola NA, Babon JJ, SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nat Struct Mol Biol (2013) Apr;20(4):469-76.